Molecular epigenetics and genetics in neuro-oncology.
Molecular epigenetics and genetics in neuro-oncology.
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DOI：
10.1016/j.nurt.2009.04.002
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Costello JF
中科院分区：
文献类型：
--
作者：
Nagarajan RP;Costello JF
胶质瘤是通过正常脑细胞的遗传和表观遗传改变而产生的，尽管每种胶质瘤亚型的确切细胞起源尚不清楚。基因表达和蛋白功能的改变导致细胞分裂失控，肿瘤扩张和浸润到周围正常的脑实质。遗传和表观遗传改变是肿瘤亚型和肿瘤级别特异性的。特定的改变可以预测肿瘤的侵袭性、肿瘤对治疗的反应和患者的生存。基因改变包括缺失、获得、扩增、突变和易位，它们导致致癌基因激活和肿瘤抑制基因失活，或者在某些情况下，这些改变可能仅仅是肿瘤发生的结果。脑肿瘤的表观遗传改变包括与肿瘤抑制基因沉默相关的CpG岛高甲基化，与异常基因激活相关的基因特异性低甲基化，以及可能导致印迹丧失、染色体不稳定和细胞过度增殖的全基因组低甲基化。其他表观遗传改变，如组蛋白变异位置的改变和组蛋白修饰的改变，在脑肿瘤的分子病理学中也可能很重要。考虑到组蛋白去乙酰化酶是已经在临床试验中的药物的靶点，令人惊讶的是，我们对原发性脑肿瘤中的组蛋白乙酰化知之甚少。虽然大多数表观遗传改变是独立于遗传改变的，但在特定基因、信号通路和染色体结构域内存在相互作用。下一代测序技术现在是基因组和表观基因组分析的首选方法，可以更全面地了解遗传和表观遗传对大脑肿瘤发生的贡献。
Gliomas arise through genetic and epigenetic alterations of normal brain cells, though the exact cell of origin for each glioma subtype is unknown. The alteration-induced changes in gene expression and protein function allow uncontrolled cell division, tumor expansion and infiltration into surrounding normal brain parenchyma. The genetic and epigenetic alterations are tumor subtype and tumor-grade specific. Particular alterations predict tumor aggressiveness, tumor response to therapy and patient survival. Genetic alterations include deletion, gain, amplification, mutation and translocation which result in oncogene activation and tumor suppressor gene inactivation, or in some instances the alterations may simply be a consequence of tumorigenesis. Epigenetic alterations in brain tumors include CpG island hypermethylation associated with tumor suppressor gene silencing, gene-specific hypomethylation associated with aberrant gene activation, and genome-wide hypomethylation potentially leading to loss of imprinting, chromosomal instability and cellular hyperproliferation. Other epigenetic alterations, such as changes in the position of histone variants and changes in histone modifications are also likely important in the molecular pathology of brain tumors. Given that histone deacetylases are targets for drugs that are already in clinical trial, surprisingly little is known about histone acetylation in primary brain tumors. While a majority of epigenetic alterations are independent of genetic alterations, there is interaction on specific genes, signaling pathways and within chromosomal domains. Next-generation sequencing technology is now the method of choice for genomic and epigenome profiling, allowing more comprehensive understanding of genetic and epigenetic contributions to tumorigenesis in the brain.
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